Numerous reports spanning two decades have confirmed umbilical cord blood (UCB) as a clinical source of hematopoietic progenitors for allogeneic transplantation in the treatment of hematologic malignancies. Despite the primary drawback of slower kinetics of myeloid engraftment as a result of limited graft cell dose, UCB has several advantages over bone marrow (BM) in a therapeutic setting, particularly the observed lowered incidence of acute graft-versus-host disease (aGVHD) despite the infusion of human leukocyte antigen (HLA) disparate grafts. aGVHD remains a major obstacle to the broader application of allogeneic stem cell therapy and is characterized by donor CD4+ T-cell activation in response to self-antigen presented by class II major histocompatibility complex (MHC) on host antigen-presenting cells (APCs). The clinical manifestation of aGVHD closely mimics the pathophysiology of autoimmune disorders with early secretion of proinflammatory cytokines including interferon γ (IFN γ), tumor necrosis factor α (TNF α), granulocyte macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-1, as well as later secretion of IL-2 by donor-derived T cells. These stimulate inflammatory cell proliferation, up-regulate MHC expression, natural killer (NK) and cytotoxic CD8+ T-cell recruitment, and widespread tissue damage particularly in the skin, large intestine, and liver.
A key transcription factor in CD4+ T-cell activation and the downstream target of cyclosporine A (CsA) treatment, nuclear factor of activated T cells, cytoplasmic 2 (NFATc2, also known as NFAT1) influences the expression of a wide array of cytokines, surface receptors, and cell cycle regulators associated with normal and autoimmune responses. Tandem interactions with other transcription factors, particularly the AP1 (fos/jun) complex occur at adjacent DNA binding sites located in the promoter regions of the genes encoding such factors as IFNγ, TNFα, IL-2, IL-4, IL-5, cytotoxic T-lymphocyte antigen 4 (CTLA-4), GM-CSF, and CD40L. Expression of many of these genes, specifically those associated with a Th2 or allergic response, is not severely diminished (and in some cases enhanced) in NFAT1-null mice, suggesting some level of redundancy among members of the NFAT family and their binding partners. However, NFAT1 has been shown to be required for the sustained production of IFNγ, GM-CSF, IL-3, IL-4, IL-2 (with API), and TNF-α indicating a critical role for NFAT1 in the initiation of a productive Th1 immune response.